# Mechanism of Protein Synthesis and Translational Control

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $50,774

## Abstract

Project Summary
 Our research program focuses on the mechanism of eukaryotic protein synthesis and translational
control. The two projects we are currently studying are: (1) the mechanism of translational control by the fragile
X mental retardation protein (FMRP), and (2) the mechanism of translation initiation on influenza A virus (IAV)
mRNAs. Fragile X syndrome is a disease that afflicts about 100,000 Americans and about 3 million people
worldwide, resulting in intellectual disability, childhood seizures, and autistic behavior in the patients. The
disease is caused by the transcriptional silencing of the fragile X mental retardation 1 gene (FMR1). FMR1 gene
codes for an RNA-binding protein, FMRP, which is highly expressed in the brain and is essential for the brain's
normal development. Mammals have two autosomal paralogs of FMRP designated as fragile X-related 1 and 2
(FXR1 and FXR2) proteins. FMRP, FXR1, and FXR2 have been implicated in regulating the translation of
several mRNAs. However, the precise mechanism by which these proteins regulate the expression of these
mRNAs is unknown. The first project aims to understand the molecular mechanism underlying the regulation of
protein synthesis by FMRP, FXR1, and FXR2. We will use a robust in vitro translation system, biochemical
techniques, and quantitative biophysical methods to significantly advance our understanding of the molecular
mechanism used by FMRP, FXR1, and FXR2 to regulate protein synthesis. The results of these studies will
provide valuable insights into identifying potential drug targets to treat Fragile X syndrome.
 The second project aims to investigate the mechanism of translation initiation by IAV mRNAs. IAV is
responsible for several thousand deaths annually and is a severe threat to global public health. We have new
data that indicate that IAV mRNAs may use a non-canonical mechanism of translation initiation. Our studies
show that poly A binding protein 1 (PABP1) binds to the highly conserved sequences in the 5'-UTR of IAV
mRNAs. Additionally, we show that the translation of the IAV mRNA is more resistant to the inactivation of
eukaryotic initiation factor 4E (eIF4E) compared to a control mRNA. We hypothesize that the recruitment of
PABP1 to the viral 5'-UTRs tethers eIF4G and promotes the assembly of the translation initiation complex in an
eIF4E-independent manner. This may favor the translation of IAV mRNAs under cellular stress conditions in the
cell, which is known to reduce the activity of eIF4E. We will determine whether the binding of PABP1 to the 5'-
UTR of IAV mRNAs is essential for translation initiation and the viral cycle using in vitro techniques and cellular
IAV infection studies. Our research will lead to fundamental new knowledge about the translation initiation
process on IAV mRNAs, which could help develop new antiviral drugs.

## Key facts

- **NIH application ID:** 11031670
- **Project number:** 3R35GM141864-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SIMPSON JOSEPH
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $50,774
- **Award type:** 3
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11031670

## Citation

> US National Institutes of Health, RePORTER application 11031670, Mechanism of Protein Synthesis and Translational Control (3R35GM141864-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11031670. Licensed CC0.

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